[18F]FDG Accumulation in Early Coronary Atherosclerotic Lesions in Pigs

Objective

Inflammation is an important contributor to atherosclerosis progression. A glucose analogue ¹⁸F-fluorodeoxyglucose ([¹⁸F]FDG) has been used to detect atherosclerotic inflammation. However, it is not known to what extent [¹⁸F]FDG is taken up in different stages of atherosclerosis. We aimed to study the uptake of [¹⁸F]FDG to various stages of coronary plaques in a pig model.

Methods

First, diabetes was caused by streptozotocin injections (50 mg/kg for 3 days) in farm pigs (n = 10). After 6 months on high-fat diet, pigs underwent dual-gated cardiac PET/CT to measure [¹⁸F]FDG uptake in coronary arteries. Coronary segments (n = 33) were harvested for ex vivo measurement of radioactivity and autoradiography (ARG).

Results

Intimal thickening was observed in 16 segments and atheroma type plaques in 10 segments. Compared with the normal vessel wall, ARG showed 1.7±0.7 times higher [¹⁸F]FDG accumulation in the intimal thickening and 4.1±2.3 times higher in the atheromas (P = 0.004 and P = 0.003, respectively). Ex vivo mean vessel-to-blood ratio was higher in segments with atheroma than those without atherosclerosis (2.6±1.2 vs. 1.3±0.7, P = 0.04). In vivo PET imaging showed the highest target-to-background ratio (TBR) of 2.7. However, maximum TBR was not significantly different in segments without atherosclerosis (1.1±0.5) and either intimal thickening (1.2±0.4, P = 1.0) or atheroma (1.6±0.6, P = 0.4).

Conclusions

We found increased uptake of [¹⁸F]FDG in coronary atherosclerotic lesions in a pig model. However, uptake in these early stage lesions was not detectable with in vivo PET imaging. Further studies are needed to clarify whether visible [¹⁸F]FDG uptake in coronary arteries represents more advanced, highly inflamed plaques.     

Transient Receptor Potential Canonical 1 (TRPC1) Channels as Regulators of Sphingolipid and VEGF Receptor Expression: IMPLICATIONS FOR THYROID CANCER CELL MIGRATION AND PROLIFERATION*

The identity of calcium channels in the thyroid is unclear. In human follicular thyroid ML-1 cancer cells, sphingolipid sphingosine 1-phosphate (S1P), through S1P receptors 1 and 3 (S1P₁/S1P₃), and VEGF receptor 2 (VEGFR2) stimulates migration. We show that human thyroid cells express several forms of transient receptor potential canonical (TRPC) channels, including TRPC1. In TRPC1 knockdown (TRPC1-KD) ML-1 cells, the basal and S1P-evoked invasion and migration was attenuated. Furthermore, the expression of S1P₃ and VEGFR2 was significantly down-regulated. Transfecting wild-type ML-1 cells with a nonconducting TRPC1 mutant decreased S1P₃ and VEGFR2 expression. In TRPC1-KD cells, receptor-operated calcium entry was decreased. To investigate whether the decreased receptor expression was due to attenuated calcium entry, cells were incubated with the calcium chelator BAPTA-AM (1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid). In these cells, and in cells where calmodulin and calmodulin-dependent kinase were blocked pharmacologically, S1P₃ and VEGFR2 expression was decreased. In TRPC1-KD cells, both hypoxia-inducible factor 1α expression and the secretion and activity of MMP2 and MMP9 were attenuated, and proliferation was decreased in TRPC1-KD cells. This was due to a prolonged G₁ phase of the cell cycle, a significant increase in the expression of the cyclin-dependent kinase inhibitors p21 and p27, and a decrease in the expression of cyclin D2, cyclin D3, and CDK6. Transfecting TRPC1 to TRPC1-KD cells rescued receptor expression, migration, and proliferation. Thus, the expression of S1P₃ and VEGFR2 is mediated by a calcium-dependent mechanism. TRPC1 has a crucial role in this process. This regulation is important for the invasion, migration, and proliferation of thyroid cancer cells.     

Fecundity selection does not vary along a large geographical cline of trait means in a passerine bird

Local environmental and ecological conditions are commonly expected to result in local adaptation, although there are few examples of variation in phenotypic selection across continent‐wide spatial scales. We collected standardized data on selection with respect to the highly variable plumage coloration of pied flycatcher (Ficedula hypoleuca Pall.) males from 17 populations across the species' breeding range. The observed selection on multiple male coloration traits via the annual number of fledged young was generally relatively weak. The main aim of the present study, however, was to examine whether the current directional selection estimates are associated with distance to the sympatric area with the collared flycatcher (Ficedula albicollis Temminck), a sister species with which the pied flycatcher is showing character displacement. This pattern was expected because plumage traits in male pied flycatchers are changing with the distance to these areas of sympatry. However, we did not find such a pattern in current selection on coloration. There were no associations between current directional selection on ornamentation and latitude or longitude either. Interestingly, current selection on coloration traits was not associated with the observed mean plumage traits of the populations. Thus, there do not appear to be geographical gradients in current directional fecundity selection on male plumage ornamentation. The results of the present study do not support the idea that constant patterns in directional fecundity selection would play a major role in the maintenance of coloration among populations in this species. By contrast, the tendency for relatively weak mosaic‐like variation in selection among populations could reflect just a snapshot of temporally variable, potentially environment‐dependent, selection, as suggested by other studies in this system. Such fine‐grained variable selection coupled with gene flow could maintain extensive phenotypic variation across populations. © 2015 The Linnean Society of London, Biological Journal of the Linnean Society, 2015, 114 , 808–827.     

Sympatric divergence and clinal variation in multiple coloration traits of Ficedula flycatchers

Geographic variation in phenotypes plays a key role in fundamental evolutionary processes such as local adaptation, population differentiation and speciation, but the selective forces behind it are rarely known. We found support for the hypothesis that geographic variation in plumage traits of the pied flycatcher Ficedula hypoleuca is explained by character displacement with the collared flycatcher Ficedula albicollis in the contact zone. The plumage traits of the pied flycatcher differed strongly from the more conspicuous collared flycatcher in a sympatric area but increased in conspicuousness with increasing distance to there. Phenotypic differentiation (P_ST) was higher than that in neutral genetic markers (F_ST), and the effect of geographic distance remained when statistically controlling for neutral genetic differentiation. This suggests that a cline created by character displacement and gene flow explains phenotypic variation across the distribution of this species. The different plumage traits of the pied flycatcher are strongly to moderately correlated, indicating that they evolve non‐independently from each other. The flycatchers provide an example of plumage patterns diverging in two species that differ in several aspects of appearance. The divergence in sympatry and convergence in allopatry in these birds provide a possibility to study the evolutionary mechanisms behind the highly divergent avian plumage patterns.     

Climate‐driven extinctions shape the phylogenetic structure of temperate tree floras

When taxa go extinct, unique evolutionary history is lost. If extinction is selective, and the intrinsic vulnerabilities of taxa show phylogenetic signal, more evolutionary history may be lost than expected under random extinction. Under what conditions this occurs is insufficiently known. We show that late Cenozoic climate change induced phylogenetically selective regional extinction of northern temperate trees because of phylogenetic signal in cold tolerance, leading to significantly and substantially larger than random losses of phylogenetic diversity (PD). The surviving floras in regions that experienced stronger extinction are phylogenetically more clustered, indicating that non‐random losses of PD are of increasing concern with increasing extinction severity. Using simulations, we show that a simple threshold model of survival given a physiological trait with phylogenetic signal reproduces our findings. Our results send a strong warning that we may expect future assemblages to be phylogenetically and possibly functionally depauperate if anthropogenic climate change affects taxa similarly.     

Triazoloquinazolines as a novel class of phosphodiesterase 10A (PDE10A) inhibitors

Novel triazoloquinazolines have been found as phosphodiesterase 10A (PDE10A) inhibitors. Structure-activity studies improved the initial micromolar potency which was found in the lead compound by a 100-fold identifying 5-(1H-benzoimidazol-2-ylmethylsulfanyl)-2-methyl-[1,2,4]triazolo[1,5-c]quinazoline, 42 (PDE10A IC₅₀ = 12 nM) as the most potent compound from the series. Two X-ray structures revealed novel binding modes to the catalytic site of the PDE10A enzyme.     

Molecular phylogeny of the Astrophorida (Porifera, Demospongiae(p)) reveals an unexpected high level of spicule homoplasy

Background

The Astrophorida (Porifera, Demospongiae ^p) is geographically and bathymetrically widely distributed. Systema Porifera currently includes five families in this order: Ancorinidae, Calthropellidae, Geodiidae, Pachastrellidae and Thrombidae. To date, molecular phylogenetic studies including Astrophorida species are scarce and offer limited sampling. Phylogenetic relationships within this order are therefore for the most part unknown and hypotheses based on morphology largely untested. Astrophorida taxa have very diverse spicule sets that make them a model of choice to investigate spicule evolution.

Methodology/Principal Findings

With a sampling of 153 specimens (9 families, 29 genera, 89 species) covering the deep- and shallow-waters worldwide, this work presents the first comprehensive molecular phylogeny of the Astrophorida, using a cytochrome c oxidase subunit I (COI) gene partial sequence and the 5′ end terminal part of the 28S rDNA gene (C1-D2 domains). The resulting tree suggested that i) the Astrophorida included some lithistid families and some Alectonidae species, ii) the sub-orders Euastrophorida and Streptosclerophorida were both polyphyletic, iii) the Geodiidae, the Ancorinidae and the Pachastrellidae were not monophyletic, iv) the Calthropellidae was part of the Geodiidae clade (Calthropella at least), and finally that v) many genera were polyphyletic (Ecionemia, Erylus, Poecillastra, Penares, Rhabdastrella, Stelletta and Vulcanella).

Conclusion

The Astrophorida is a larger order than previously considered, comprising ca. 820 species. Based on these results, we propose new classifications for the Astrophorida using both the classical rank-based nomenclature (i.e., Linnaean classification) and the phylogenetic nomenclature following the PhyloCode, independent of taxonomic rank. A key to the Astrophorida families, sub-families and genera incertae sedis is also included. Incongruences between our molecular tree and the current classification can be explained by the banality of convergent evolution and secondary loss in spicule evolution. These processes have taken place many times, in all the major clades, for megascleres and microscleres.